Review
DRUG PHOTOSENSITIZATION MICHAEL JARRATT, M.D.
Photosensitization of the skin by crude psoralen extracts from plants was recorded as early as 1400 B.C. in the ancient Indo-lranian book of sacred hymns and incantations called the Atharvaveda.i Treatment of leukoderma with the psoralen-containing plant Psoralea corylifolia appears in manuscripts from Eastern Turkistan, India, China and Egypt.2 Today, psoralens are only one of many naturally occurring and synthetic drugs commonly used in modern medical practice. Table 1 is a list of the most common photosensitizing drugs currently in use. More comprehensive listings of photosensitizing agents are found in the literature.^-•*
From the Department of Dermatology, Baylor College of Medicine, Texas Medical Center, Houston, Texas
photosensitization may occur within minutes to hours after the first exposure to the drug; however, relatively large threshold doses of drug and light must be reached in order for photosensitization to be manifest. Phototoxic reactions are characterized clinically by a noneczematous, enhanced sunburn response which is limited sharply to sun-exposed areas. Likewise, photopatch testing with a phototoxic drug results in an enhanced erythema response limited sharply to the exposed area.*^ Photoallergic reactions result from a more complex process involving photoconversion of the drug into a haptene, which binds with skin protein to form a complete photoantigen. The photoantigen then is transported to regional lymph nodes where true lymphocytemediated allergic sensitization ensues. It also is possible that circulating lymphoid cells pick up antigenic information from fixed allergen-skin protein conjugates and return to "seed" the lymph nodes. Only a small percentage of the population at risk will develop true allergic hypersensitivity to the photoantigen;
Photosensitization of the skin may occur through 2 pathways—phototoxicity and photoallergys (Fig. 1). Phototoxic reactions are induced by photoactive drugs which absorb light energy and then contribute that energy to photochemical reactions which damage cellular DNA, cytoplasmic organelles or the cell membrane. Phototoxic reactions will occur in any individual in whom a sufficient concentration of drug and a sufficient dose of light energy are delivered to the skin. Thus, the incidence of phototoxic reactions is relatively high in any population receiving a particular drug and light. Since phototoxic responses are due to an immediate photochemical reaction,
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Table 1. Common Photosensitizing Drugs , Sulfanilamide Sulfonylureas Carbutamide Tolbutamide Chlorpropamide .Thiazide diuretics Chlorothiazide Hydrochlorothiazide Phenothiazines Chlorpromazine Promethazine Criseofulvin " ,;
Tetracyclines Demethylchlortetracycline Doxycycline Oxytetracycline Tetracycline HCI Psoralens 8-methoxypsoralen Trimethylpsoralen Cyclamates Saccharin Nalidixic acid Vinblastine
hence, the incidence of photoallergic reactions is small. Eurthermore, the incubation period between ingestion of drug and manifestation of clinical photoallergy is 7 to 10 days. Once allergic sensitization is established, very small concentrations of drug and small doses of light energy will precipitate a reaction. Photoallergic eruptions are eczematous in nature and frequently extend beyond !the sun-exposed areas. Likewise, photopatch testing with the sensitizing drug will result in an eczematous eruption which extends beyond the photopatch
PHOTOTOXICITY
PHOTOALLERGY
DRUG Light
DRUG Light
.
4,
PHOTO-EXCITED DRUG (High energy state)
4.
4.
PHOTO-ALTERED DRUG (Haptene)
-1-
^
RELEASE OF ABSORBED ENERGY IN SKIN
SKIN PROTEIN
4.
COMPLETE PHOTO-ANTIGEN
4,
ENHANCED SUNBURN RESPONSE 4ALLERGIC SENSITIZATION :/ •-. ^^. ' TO PHOTO-ANTIGEN
Fig. 1. Proposed mechanisms for phototoxic and photoallergic reactions.
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The most notorious photoaliergy-inducing drugs are topically applied antibacterial agents, the halogenated salicylanilides. However, these agents have been removed, for the most part, from the modern clinical scene. Thus, they are not as common a problem as they were 10 years ago.'^ Sulfa Drugs The first description of drug phototoxicity and photoallergy came from Stephan Epstein in 1939.'^ He injected normal volunteers intradermally with sulfanilamide and irradiated the injection sites. Within a few hours, he observed an erythematous phototoxic response. In 10 days, the same volunteers manifested more quickly developing urticarial responses to much smaller doses of drug and light; this was interpreted as photoallergy. Bloom^" and Burckhardt" confirmed these studies in 1941. The exact nature of the sulfonamideinduced phototoxic and photoallergic reactions still is unknown. An oxidation product of sulfanilamide, p-hydroxyaminobenzene sulfonamide, when injected intradermally, results in an immediate inflammatory response with local increases of acid phosphatase and histamine.^2 Thus, we may speculate that a photo-oxidation product of sulfanilamide may be responsible for the immediate phototoxic reaction. The demonstration of photochemical coupling of sulfonamides with egg albumin and other high molecular-weight conjugates to form allergens supports the photoallergy concept outlined previously." The wavelength of light which is responsible for inciting the sulfonamide photosensitivity reaction is still a matter of debate; however, it definitely has been shown that the sulfonamide reaction can be induced by longwave ultraviolet light which passes through window glass.i^' ^^
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•
0.
•
319
^0
S02-NHC0NH
Fig. 2. The photosensitizing sulfonamide derivatives.
CH2 H2N
H2N
CH CH»
SULFANILAMIDE
Thiazide Diuretics The thiazide diuretics (chlorothiazide and hydrochlorothiazide) are sulfonamide derivatives (Fig. 2). Photoeruptions induced by the thiazides may be sunburn-like, eczematous or lichen planus-like."' The photoeruptions resolve upon discontinuation of the drug, and subsequent challenge with light exposure without drug does not induce an eruption. However, Harber, Lashinsky and Baer'^ reported 3 patients in whom oral readministration of thiazides followed by light exposure in a limited photopatch test area resulted in local erythema and edema followed by a flare of previously erupted areas protected from light. This phenomenon is an argument for photoallergy rather than for simple phototoxicity. These authors indicated that the action spectrum for the reaction was 275 to 310 nm. However, their testing was done with a carbon arc source which induced no reaction through window glass. More recent studies indicate that, although the reaction induced by sunlight is markedly decreased by window glass, abnormal erythema reactions can be induced with intradermal chlorothiazide and sunlight through a Mylar filter transmitting only wavelengths longer than 310 nm.^^ Sulfonylureas
CHLOROTHIAZIDE
SULFONYLUREA
scription of an erythematous, edematous and blistering eruption to carbutamide and light.^'^ Burckhardt et al. reproduced the eruption w i t h photopatch testing. Sams,-o and Hitselberger and Fosnough-i subsequently reported photosensitizat i o n to b o t h t o l b u t a m i d e and c h l o r p r o pamide. Hitselberger considered the reaction a photoallergic p h e n o m e n o n because of the eczematous nature of the e r u p t i o n and because of the l o w incidence of photosensitization to the sulfonylurea drugs. Willis and Kligman induced positive photopatch tests in volunteer subjects w i t h t o l b u t a m i d e and a zenon arc
CARBUTAMIDE (Nadisan)
SO2NHCONH
TOLBUTAMIDE (Orinase)
,
Sulfonylurea oral hypoglycemic agents represent another modification of the sulfonamide molecule (Fig. 3). The first report of photosensitization to the sulfonylureas came in 1957 w i t h the d e -
CHLORPROPAMIDE (Diabinese) Fig. 3. The sulfonylurea oral hypoglycemic agents.
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Vol. 15
CI
N PHENOTHIAZINE
METHYLENE BLUE
Fig. 4. The photosensitizing phenothiazine derivatives.
S
:
rt3)2
CH3
CHLORPROMAZINE (THORAZINE)
CH-CH-N
PROMETHAZINE (PHENERGAN)
light source through window glass, thus indicating that photoreactions may be induced with longwave ultraviolet light.i^ Phenothiazines and Antihistamines The first report of phenothiazine photosensitization came in 1940 when farm workers using phenothiazine as an insecticide spray developed photodermatitis.22 Since then, the phenothiazine derivatives have gained very wide use as systemically administered psychotherapeutic agents. Photoeruptions occur in 3% to 12% of all patients taking phenothiazines orally.^^^ 2.'; Chlorpromazine is the most common offender: however, photosensitization to prochlorperazine, mepazine, trimeprazine and promethazine is reported.'' The large tnajority of phenothiazineinduced photoeruptions occurs in the summer months after sustained exposure to strong sunlight.2''' 27 Therefore, one would assume that these reactions are phototoxic in nature, since large doses of light energy are required to elicit a response. However, it has been shown experimentally that photoreactions to chlorpromazine may be both phototoxic and photoallergic. Epstein demonstrated with chlorpromazine photopatch tests an early erythematous re-
action occurring in less than 24 hours confined to the patch test site; however, 6 to 9 days later, an eczematous reaction extending beyond the patch test sites was elicited.28 Hence, as in the case with sulfonamide, initial phototoxic reactions to chlorpromazine may be followed by true allergic sensitization. Although large doses of sunburn radiation (290-310 nm) may be required to elicit the more common phenothiazine phototoxic reactions, Sams, Epstein, Kligman, and Breit demonstrated positive photopatch tests with longwave ultraviolet light as well.IS' i« The antihistamine promethazine is a phenothiazine derivative closely related to chlorpromazine (Fig. 4). Photo cross-reaction between promethazine and chlorpromazine has been demonstrated.^^^ ^o Positive photopatch testing to nonphenothiazine antihistamines also has been elicited with a carbon arc lamp (2500-7000A) and diphenhydramine, bromodiphenhydramine, chlorpheniramine and carbinoxamine." Tetracyclines Demethylchlortetracycline was introduced for general clinical use in 1958. Soon thereafter, numerous reports of photosensitive reactions to the drug ap-
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DRUG PHOTOSENSITIZATION • 7arra(f
CH3
OH
321
OH
6
0H°" 0 CH3
TETRACYCLINE OH
Fig. 5. All of the tetracyclines except minocycline have significant photosensitizing potential.
OH
0
OH
CH3
N
0
CHLORTETRACYCLINE .H3
CH3
CONH, OH
0
OH
0
DOXYCYCLINE
peared.32,33 vVith attention thus focused on the photosensitizing capacity of demethylchlortetracycline, closer scrutiny of other tetracyclines revealed photosensitive reactions and photoonycholysis due to other tetracycline derivatives.•^•* Originally, it was thought that the presence of a chlorine atom at position 7 and the absence of a methyl radical at position 6 were prerequisites for photosensitizing capacity.-^-'' However, later studies revealed that doxycycline, which differs from the basic tetracycline structure only in the absence of a hydroxyl group at position 6, has a significant phototoxic potential-^*^ (Eig. 5). Studies of demethylchlortetracycline by Orentreich, Harber, Tromavitch, Baer, Kligman, and others'"-'' indicated that the mechanism of photosensitization was phototoxicity rather than photoallergy. They based this conclusion on the high incidence of photosensitive reactions with demethylchlortetracycline, the sunburn-like reaction with no eczematization in photopatch test sites, and the quick reversibility of photosensitivity upon discontinuing the drug. Later, however, Tromavitch and Jacobs reported a pa-
OH
0
OH
OHll 0
MINOCYCLINE
tient in whom a photoeruption developed while taking oxytetracycline, in whom photosensitivity persisted 6 months after discontinuing the drug, and in whom phototest sites were eczematous in nature, accompanied by distant flares of eczematous dermatitis.^" Thus, it appears that, although the vast majority of tetracycline-photosensitive reactions are phototoxic in nature, development of true photoallergic hypersensitivity to tetracycline occasionally may be seen. Some studies to determine the action spectrum for tetracycline photosensitive reactions indicate that middle range ultraviolet light (290-320 nm; UVB) is responsible.^' However, these studies were done with artificial light sources which apparently produced insufficient amounts (320-400 nm; UVA) of longwave ultraviolet light to induce reactions, since patients have been reported who developed photosensitive eruptions to demethylchlortetracycline through window glass^-' •'•' Other studies demonstrated phototoxic reactions to intradermal tetracycline and demethylchlortetracycline in human volunteers with natural sunlight
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through window glass, but not with artificial light sources through window glass or Mylar.'*'*' ''•'' Stratigos and Magnus""' demonstrated with a monochromator positive phototoxic reactions to intradermal demethylchlortetracycline with light between 350 and 420 nanometers. Griseofuivin Patients taking griseofuivin, when exposed to significant doses of natural sunlight, will develop exaggerated sunburn reactions. Lamb and colleagues^'' demonstrated, in patients taking griseofuivin, enhanced erythema responses to artificial UVB and 2-f erythema responses to artificial ultraviolet light through window glass.'•" Administration of griseofuivin to mice induces increased hepatic synthesis of protoporphyrin and increased fecal excretion of protoporphyrin and coproporphyrin.4R. ^g j h e drug also induces synthesis of delta-aminolevulinic acid synthetase in tissue cultures of chick embryo liver cells.so Hence, it has been proposed that the photosensitivity induced by griseofuivin might be due to induction of an artificial erythropoietic protoporpbyria-like state. However, it has never been conclusively demonstrated that oral administration of griseofuivin to humans results in the same induction of excess porphyrin synthesis as seen in mice.^'' ^2 The maximum absorption spectrum of griseofuivin falls in the sunburn spectrum. Thus, it seems more tenable to ascribe the photosensitivity induced by griseofuivin to a simple photodynamic mechanism. • Psoralens
As already recounted, naturally occurring psoralens were known for their photosensitizing capacity in ancient
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India, Central Asia and Egypt. More recently, modern physicians have become aware of the hyperpigmented berloque dermatitis seen in women caused by psoralens in perfume. And, in 1951, bullous photoreactions were reported among celery harvesters who contacted psoralens in pink rot fungus on celery plants." Most phototoxic reactions discussed earlier in this paper are photodynamically induced by a photoactive molecule which absorbs light energy and then contributes that energy to an oxidation reaction involving molecular oxygen. Psoralen phototoxicity, however, is partially inhibited by the presence of molecular oxygen.54 The psoralen molecule in the presence of longwave ultraviolet light photo-binds to thymine in cellular DNA and thus shuts down DNA synthesis." Although the psoralen absorption peaks are at 250 and 300 nm the action spectrum for psoralen phototoxicity falls in a range between 320 and 370 nm.''^''^ The usual phototoxic reaction induced by psoralen and longwave ultraviolet light is a non-eczematous, enhanced sunburn erythema which reaches its peak between 48 and 72 hours after exposure. Curiously, however, eczematous photoallergic reactions to 8-methoxypsoralen have been reported as well.^' Psoralens have been used for many years in the treatment of vitiligo. In the last 3 years, psoralens and longwave ultraviolet light have been found useful in the treatment of psoriasis. Originally, 8-methoxypsoralen was applied topically to psoriatic plaques and irradiated with black light. Although this mode of therapy induced resolution of psoriatic plaques, it also left a residual cosmetically objectionable hyperpigmentatjon.co- Cl Most recently, 8-methoxypsoralen has been administered orally and
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DRUG PHOTOSENSITIZATION • Jarratt
followed by longwave ultraviolet irradiation in a closet-like light box.'*- This mode of therapy for psoriasis is still under investigation; however, initial studies are encouraging. Miscellaneous Drugs Both of the commonly used artificial sweeteners have induced photosensitive reactions. Cyclamates caused eczematous photoeruptions in patients in whom the lesions could be reproduced by oral ingestion of cyclamates and light or by photo-patch testing with cyciamates. The same photosensitive reactions could not be induced in normal volunteers,'''-''^ Because of the low incidence of photoreactions to cyclamates and because of inability to reproduce similar lesions in normal volunteers, it can be assumed that the reported reactions are photoallergic in nature. Four patients are reported to have developed photosensitive reactions while using saccharin.'''^ Photoxic bullous eruptions due to nalidixic acid may develop after extensive sun exposure. In some cases, blisters continue to form for weeks after the drug is discontinued.^''-'5^ Drug Names bromodipbenbydramine: Ambrodryl carbinoxmine: Twiston-RA carbutamide: Nadisan chlorpromazine: Thorazine chlorpro[3amide: Diabinese , demetbylchlortetracycline: Declomycin dipbenbydramine: Benadryl doxycycline: Doxy II, Vibramycin 8 MOP {8-methoxypsoralen): Oxsoralen mepazine: Pacatal minocycline: MInocin, Vectrin nalidixic acid: NegGram procblorperazine: Compazine promethazine: Phenergan tolbutamide: Orinase trioxsalen {4, 5', 8-trimethylpsoralen): Trisoralen vinblastine: Velban
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References 1, Fitzpatrick, T, B,, and Pathak, M, A,, Historical aspects of methoxsalen and otber furocoumarins, J, Invest, Dermatol, 32:229, 1959, 2, Fahmy, I, R,, and Abu-Sbady, H,, Ammi majus linn: Pbarmacognostical study and isolation of crystalline constituent, Ammoidin, Quart. J, Pharm, Pharmacol, 20:281, 1947, 3, Kalivas, J,, A guide to tbe problem of photosensitivity, JAMA 209:1706, 1969, 4, Sams, W, M,, Photosensitizing therapeutic agents, JAMA 174:2043, 1960, 5, Kirscbbaum, B, A,, and Beerman, H,, Pbotosensitization due to drugs. Am, J, Med Sci 248:445, 1964, 6, Harber, L, G,, and Baer, R, L,, Pathogenic mechanism of drug-induced photosensitivity, J, Invest, Dermatol, 58:327, 1972, 7, Storck, H,, Photoallergy and pbotosensitivity. Arch, Dermatol, 91:469, 1965, 8, Freeman, R, G,, and Knox, J, M,, The action spectrum of photocontact dermatitis caused by halogenated salicylanilide and related compounds. Arch, Dermatol, 97:130, 1968, 9, Epstein, S,, Pbotoallergy and primary pbotosensitivity to sulfanilamide, J, Invest, Dermatol, 2:43, 1939, 10, Bloom, H, F,, Studies of photosensitivity due to sulfanilamide, J, Invest, Dermatol, 4-159 1941, 11, Burckbardt, W,, Untersucbungen uber die photoaktivitat einiger sulphanilamide, Dermatologica 83:63, 1941, 12. Aoki, K,, and Saito, T,, Studies on the mechanism of photosensitivity caused by sulfa drugs. In Sunlight and Man, Edited by Fitzpatrick, T, B. Tokyo, University of Tokyo Press, 1974, pp, 431-444, 13. Sulser, H,, Photocbemische kupplung des sulfanilamids und aromatiscber amine an eiweiss und andere bocbmolekulare verbindungen, Arcb, Klin, Exper, Dermatol, 215: 266, 1962, 14, Willis, I,, and Kligman, A, M,, Diagnosis of pbotosensitization reactions by the scotch tape provocative patch test. J. Invest. Dermatol, 51:116, 1968, 15, Kligman, A, M,, and Breit, R,, Identification of pbototoxic drugs by buman assay. J. Invest, Dermatol, 51:90, 1968, 16. Burckbardt, W,, and Sutter, T. (Photoallergic drug exanthema caused by bydrocblorothiazide), Z, Haut Geschlechtskr. 34:105, 1963. 17. Harber, L G,, Lashinsky, A, M., and Baer, R, L,, Skin manifestations of pbotosensitivity due to cblorthiazide and hydrocblorothiazide, J, Invest, Dermatol, 33:83, 1959,
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18. Sams, W. M., Jr., and Epstein, J. H., The experimental production of drug phototoxicity in guinea pigs. I. Using sunlight. J. Invest. Dermatol. 48:89, 1967. 19. Burckhardt, W., Burckhardt, K., and SchwarzSpeck, M., Photoallergic eczemas caused by carbutamide (Nadisan). Schweiz. Med. Wchnschr. 87:954, 1957. 20. Sams, W. M., Photosensitizing therapeutic agents. JAMA 174:2043, 1960. 21. Hitselberger, J. F., and Fosnaugh, R. P., Photosensitivity due to chlorpropamide. JAMA 180:62, 1962. 22. De Eds, F., Wilson, R. H., and Thomas, J. O., Photosensitization by phenothiazine. JAMA 114:2095, 1940. 23. Winkelman, N. W., Jr., An appraisal of chlorpromazine. Am. J. Psychiatr. 113:961, 1957. 24. Epstein, J. H., Brunsting, L. A., Petersen, M. C, and Schwarz, B. E., Study of photosensitivity occurring with chlorpromazine therapy. J. Invest. Dermatol. 28:329, 1957. 25. Ayd, F. J., Jr., The dermatologic and systemic manifestations of chlorpromazine hypersensitivity. J. Nerv. Mental Dis. 124:84, 1956. 26. Cahn, M. M., and Levy, E. J. Ultraviolet light factor in chlorpromazine dermatitis. Arch. Dermatol. Syphilol. 75:38, 1957. 27. Cohen, 1. M., and Nash, J. B., Photosensitization by chlorpromazine. Psychlat. Res. Rep. 1:11, 1955. 28. Epstein, S., Chlorpromazine photosensitivity: Phototoxic and photoallergic reactions. Arch. Dermatol. 98:354, 1968. 29. Epstein, S., and Rowe, R. J., Photoallergy and photocross-sensitivity to phenergan. J. Invest. Dermatol. 29:319, 1957. 30. Newill, R. C. D., Photosensitivity caused by Promethazine. Br. Med. J. 2:359, 1960. 31. Schreiber, M. M., and Naylor, L. Z., Antihistamine pbotosensitivity. Arch. Dermatol. 86:58, 1962. 32. Morris, W. E., Photosensitivity due to tetracycline derivative. JAMA 172:1155, 1960. 33. Falk, M. S., Light sensitivity due to demethychlortetracycline. JAMA 172:1156, 1960. 34. Segal, B. M., Photosensitivity, nail discoloration and onycholysis: Side effects of tetracycline therapy. Arch. Int. Med. 112:165, 1963. 35. Tanioku, K., and Ono, K., Phototoxic and photoallergic problems. In Sunlight and Man. Edited by Fitzpatrick, T. B. Tokyo, University of Tokyo Press, 1974, pp. 483-493.
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36. Frost, P., Weinstein, C. D., and Comez, E. C, Phototoxic potential of minocycline and doxycycline. Arch. Dermatol. 105:681, 1972. 37. Orentreich, N., Harber, L. C, and Tromovitch, T. A., Photosensitivity and photo-onycholysis due to demethylcblortetracycline. Arch. Dermatol. 83:730, 1961. 38. Harber, L. C, Tromovitch, T. A., and Baer, R. L., Studies on photosensitivity due to demethylchlortetracycline. J. Invest. Dermatol. 37:189, 1961. 39. Kligman, A. M., Declomycin Compendium. Pearl River, New York, Lederle Pharmaceuticals, 1962, p. 49. 40. Tromovitcb, T. A., and Jacobs, P. H., Photosensitivity to oxytetracycline. Ann. Int. Med. 58:529, 1963. 41. Sams, W. M., The experimental production of drug phototoxicity in guinea pigs. II. Using artificial light sources. Arch. Dermatol. 94:773, 1966. 42. Saslaw, S., Demethylchlortetracycline pbototoxicity. N. EngI. J. Med. 264:1301, 1961. 43. Fubrmann, D. L., and Drowns, B. V., Demethylchlortetracycline: Clinical aspect of its use in dermatology. Arch. Dermatol. 82:244, 1960. 44. Schorr, W. F., and Monash, S., Photo-irradiation studies of two tetracyclines. Arch. Dermatol. 88:440, 1963. 45. Maibach, H. I., Sams, W. M., and Epstein, J. H., Screening for drug toxicity by wavelengths greater than 3100 A. Arch. Dermatol. 95:12, 1967. 46. Stratigos, J. D., and Magnus, I. A., Photosensitivity by demethylchloretracycline and sulphanilamide. Br. J. Dermatol. 80:391, 1968. 47. Lamb, J. H., Jones, P. E., Morgan, R. J., et al.. Further studies on light sensitive eruptions. Arch. Dermatol. 83:568, 1961. 48. DeMatteis, F., and Rimington, C, Disturbance of porphyrin metabolism caused by griseofulvin in mice. Br. J. Dermatol. 75:91, 1963. 49. Lockhead, A. C, Dagg, J. H., and Coldberg, A., Experimental griseofulvin porphyria in adult and fetal mice. Br. J. Dermatol. 79:96, 1967. 50. Cranick, S., The induction in vitro of the synthesis of delta-aminolevulinic acid synthetase in chemical porpbyria: A response to certain drugs, sex hormones and foreign chemicals. J. Biol. Cbem. 241:1359, 1966. 51. Rimington, C, Morgan, P. N., Nicholls, K., et al., Criseofulvin administration and porphyrin metabolism. Lancet 2:318, 1963.
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52. Watson, C. |., Lynch, F., Bossenmaier, I., and Cardinal, R., Criseofulvin and porphyrin metabolism. Arch. Dermatol. 98:451, 1968. 53. Birmingham, D. ]., Key, M. M., Tubich, C. E., and Perone, V. B., Phototoxic bullae among celery harvesters. Arch. Dermatol. 83:73, 1961. 54. Matbews, M. M., Comparative study of lethal photosensitization of Carcina lutea by 8metboxypsoralen and by Toluidine blue. J. Bacteriol. 85:322, 1963. 55. Pathak, M. A., Kriamer, D. M., and Fitzpatrick, T. B., Photobiology and photochemistry of furocoumerius. In Sunlight and Man. Edited by Fitzpatrick, T. B. Tokyo, University of Tokyo Press, 1974, pp. 335-368. 56. Buck, H. W., Magnus, I. A., and Porter, A. D., The action spectrum of 8-methoxypsoralen for erythema in human skin. Br. J. Dermatol. 72:249, 1960. 57. Pathak, M. A., Mechanisms of psoralen pbotosensitization. J. Invest. Dermatol. 37: 397, 1961. 58. Owens, D. W., Glicksman, I. M., Freeman, R. C , and Carnes, R., Biologic action spectra of 8-metboxypsoralen determined by monocbromatic light. J. Invest. Dermatol. 51:435, 1968. 59. Fulton, J. E., and Willis, I., Photoallergy to methoxsalen. Arcb. Dermatol. 98:445, 1968.
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60. Walter, J. E., and Voorhees, J. J., Psoriasis improved by psoralen plus black light. Acta Derm. Venereol. 53:469, 1973. 61. Weber, C , Combined 8-methoxypsoralen and black light therapy of psoriasis. Br. J. Dermatol. 90:317, 1974. 62. Parrish, J. A., Fitzpatrick, T. B., Tanenbaum, L., and Pathak, M. A., Pbotochemotherapy of psoriasis witb oral metboxsalen and longwave ultraviolet light. N. EngI. J. Med. 291:1207, 1974. 63. Lamberg, S. I., A new pbotosensitizer: The artificial sweetener cyciamate. JAMA 201: 747, 1967. 64. Yong, J. M., and Sanderson, K. V., Pbotosensitive dermatitis and renal tubular acidosis after ingestion of calcium cyciamate. Lancet 2:1273, 1969. 65. Kobori, ]., and Araki, H., Pbotoallergy in dermatology. J. Asthma Res. 3:213, 1966. 66. Kennedy, B., O'Quinn, S., Perret, W. |., et al., Pbototoxic and pbotoallergic skin reactions from modern drug tberapy. \. La. Med. Soc. 113:365, 1961. 67. Birkett, D. A., Garretts, M., and Stevenson, C. J., Pbototoxic bullous eruptions due to nalidixic acid. Br. J. Dermatol. 81:342, 1969. 68. Ramsay, C, and Obresbkova, E., Pbotosensitivity from nalidixic acid. Br. J. Dermatol. 91:523, 1974.
Skip another two thousand years: staphylococci are being fought with copper to this very day. There is a staphylococcal skin infection called impetigo. In France at least, a very popular—and, 1 am told, practically indispensable—prescription against impetigo is the Eau Dalibour. It was devised around the year 1700 by Monsieur Jacques Dalibour, surgeon general to the army of Louis XIV. Its principal ingredients are copper and zinc, and it worked like a charm for "all Manners of Wounds, Cuts, Slashes by Sword or Sabre, and Injuries by all Cutting and Bruising Devices."—Majno, C, The Heating Hand: Man and Wound in the Ancient World. Cambridge, MA, Harvard University Press, 1975, p. 113-115.
DRUG PHOTOSENSITIZATION MICHAEL JARRATT, M.D.
Photosensitization of the skin by crude psoralen extracts from plants was recorded as early as 1400 B.C. in the ancient Indo-lranian book of sacred hymns and incantations called the Atharvaveda.i Treatment of leukoderma with the psoralen-containing plant Psoralea corylifolia appears in manuscripts from Eastern Turkistan, India, China and Egypt.2 Today, psoralens are only one of many naturally occurring and synthetic drugs commonly used in modern medical practice. Table 1 is a list of the most common photosensitizing drugs currently in use. More comprehensive listings of photosensitizing agents are found in the literature.^-•*
From the Department of Dermatology, Baylor College of Medicine, Texas Medical Center, Houston, Texas
photosensitization may occur within minutes to hours after the first exposure to the drug; however, relatively large threshold doses of drug and light must be reached in order for photosensitization to be manifest. Phototoxic reactions are characterized clinically by a noneczematous, enhanced sunburn response which is limited sharply to sun-exposed areas. Likewise, photopatch testing with a phototoxic drug results in an enhanced erythema response limited sharply to the exposed area.*^ Photoallergic reactions result from a more complex process involving photoconversion of the drug into a haptene, which binds with skin protein to form a complete photoantigen. The photoantigen then is transported to regional lymph nodes where true lymphocytemediated allergic sensitization ensues. It also is possible that circulating lymphoid cells pick up antigenic information from fixed allergen-skin protein conjugates and return to "seed" the lymph nodes. Only a small percentage of the population at risk will develop true allergic hypersensitivity to the photoantigen;
Photosensitization of the skin may occur through 2 pathways—phototoxicity and photoallergys (Fig. 1). Phototoxic reactions are induced by photoactive drugs which absorb light energy and then contribute that energy to photochemical reactions which damage cellular DNA, cytoplasmic organelles or the cell membrane. Phototoxic reactions will occur in any individual in whom a sufficient concentration of drug and a sufficient dose of light energy are delivered to the skin. Thus, the incidence of phototoxic reactions is relatively high in any population receiving a particular drug and light. Since phototoxic responses are due to an immediate photochemical reaction,
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Table 1. Common Photosensitizing Drugs , Sulfanilamide Sulfonylureas Carbutamide Tolbutamide Chlorpropamide .Thiazide diuretics Chlorothiazide Hydrochlorothiazide Phenothiazines Chlorpromazine Promethazine Criseofulvin " ,;
Tetracyclines Demethylchlortetracycline Doxycycline Oxytetracycline Tetracycline HCI Psoralens 8-methoxypsoralen Trimethylpsoralen Cyclamates Saccharin Nalidixic acid Vinblastine
hence, the incidence of photoallergic reactions is small. Eurthermore, the incubation period between ingestion of drug and manifestation of clinical photoallergy is 7 to 10 days. Once allergic sensitization is established, very small concentrations of drug and small doses of light energy will precipitate a reaction. Photoallergic eruptions are eczematous in nature and frequently extend beyond !the sun-exposed areas. Likewise, photopatch testing with the sensitizing drug will result in an eczematous eruption which extends beyond the photopatch
PHOTOTOXICITY
PHOTOALLERGY
DRUG Light
DRUG Light
.
4,
PHOTO-EXCITED DRUG (High energy state)
4.
4.
PHOTO-ALTERED DRUG (Haptene)
-1-
^
RELEASE OF ABSORBED ENERGY IN SKIN
SKIN PROTEIN
4.
COMPLETE PHOTO-ANTIGEN
4,
ENHANCED SUNBURN RESPONSE 4ALLERGIC SENSITIZATION :/ •-. ^^. ' TO PHOTO-ANTIGEN
Fig. 1. Proposed mechanisms for phototoxic and photoallergic reactions.
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The most notorious photoaliergy-inducing drugs are topically applied antibacterial agents, the halogenated salicylanilides. However, these agents have been removed, for the most part, from the modern clinical scene. Thus, they are not as common a problem as they were 10 years ago.'^ Sulfa Drugs The first description of drug phototoxicity and photoallergy came from Stephan Epstein in 1939.'^ He injected normal volunteers intradermally with sulfanilamide and irradiated the injection sites. Within a few hours, he observed an erythematous phototoxic response. In 10 days, the same volunteers manifested more quickly developing urticarial responses to much smaller doses of drug and light; this was interpreted as photoallergy. Bloom^" and Burckhardt" confirmed these studies in 1941. The exact nature of the sulfonamideinduced phototoxic and photoallergic reactions still is unknown. An oxidation product of sulfanilamide, p-hydroxyaminobenzene sulfonamide, when injected intradermally, results in an immediate inflammatory response with local increases of acid phosphatase and histamine.^2 Thus, we may speculate that a photo-oxidation product of sulfanilamide may be responsible for the immediate phototoxic reaction. The demonstration of photochemical coupling of sulfonamides with egg albumin and other high molecular-weight conjugates to form allergens supports the photoallergy concept outlined previously." The wavelength of light which is responsible for inciting the sulfonamide photosensitivity reaction is still a matter of debate; however, it definitely has been shown that the sulfonamide reaction can be induced by longwave ultraviolet light which passes through window glass.i^' ^^
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•
0.
•
319
^0
S02-NHC0NH
Fig. 2. The photosensitizing sulfonamide derivatives.
CH2 H2N
H2N
CH CH»
SULFANILAMIDE
Thiazide Diuretics The thiazide diuretics (chlorothiazide and hydrochlorothiazide) are sulfonamide derivatives (Fig. 2). Photoeruptions induced by the thiazides may be sunburn-like, eczematous or lichen planus-like."' The photoeruptions resolve upon discontinuation of the drug, and subsequent challenge with light exposure without drug does not induce an eruption. However, Harber, Lashinsky and Baer'^ reported 3 patients in whom oral readministration of thiazides followed by light exposure in a limited photopatch test area resulted in local erythema and edema followed by a flare of previously erupted areas protected from light. This phenomenon is an argument for photoallergy rather than for simple phototoxicity. These authors indicated that the action spectrum for the reaction was 275 to 310 nm. However, their testing was done with a carbon arc source which induced no reaction through window glass. More recent studies indicate that, although the reaction induced by sunlight is markedly decreased by window glass, abnormal erythema reactions can be induced with intradermal chlorothiazide and sunlight through a Mylar filter transmitting only wavelengths longer than 310 nm.^^ Sulfonylureas
CHLOROTHIAZIDE
SULFONYLUREA
scription of an erythematous, edematous and blistering eruption to carbutamide and light.^'^ Burckhardt et al. reproduced the eruption w i t h photopatch testing. Sams,-o and Hitselberger and Fosnough-i subsequently reported photosensitizat i o n to b o t h t o l b u t a m i d e and c h l o r p r o pamide. Hitselberger considered the reaction a photoallergic p h e n o m e n o n because of the eczematous nature of the e r u p t i o n and because of the l o w incidence of photosensitization to the sulfonylurea drugs. Willis and Kligman induced positive photopatch tests in volunteer subjects w i t h t o l b u t a m i d e and a zenon arc
CARBUTAMIDE (Nadisan)
SO2NHCONH
TOLBUTAMIDE (Orinase)
,
Sulfonylurea oral hypoglycemic agents represent another modification of the sulfonamide molecule (Fig. 3). The first report of photosensitization to the sulfonylureas came in 1957 w i t h the d e -
CHLORPROPAMIDE (Diabinese) Fig. 3. The sulfonylurea oral hypoglycemic agents.
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CI
N PHENOTHIAZINE
METHYLENE BLUE
Fig. 4. The photosensitizing phenothiazine derivatives.
S
:
rt3)2
CH3
CHLORPROMAZINE (THORAZINE)
CH-CH-N
PROMETHAZINE (PHENERGAN)
light source through window glass, thus indicating that photoreactions may be induced with longwave ultraviolet light.i^ Phenothiazines and Antihistamines The first report of phenothiazine photosensitization came in 1940 when farm workers using phenothiazine as an insecticide spray developed photodermatitis.22 Since then, the phenothiazine derivatives have gained very wide use as systemically administered psychotherapeutic agents. Photoeruptions occur in 3% to 12% of all patients taking phenothiazines orally.^^^ 2.'; Chlorpromazine is the most common offender: however, photosensitization to prochlorperazine, mepazine, trimeprazine and promethazine is reported.'' The large tnajority of phenothiazineinduced photoeruptions occurs in the summer months after sustained exposure to strong sunlight.2''' 27 Therefore, one would assume that these reactions are phototoxic in nature, since large doses of light energy are required to elicit a response. However, it has been shown experimentally that photoreactions to chlorpromazine may be both phototoxic and photoallergic. Epstein demonstrated with chlorpromazine photopatch tests an early erythematous re-
action occurring in less than 24 hours confined to the patch test site; however, 6 to 9 days later, an eczematous reaction extending beyond the patch test sites was elicited.28 Hence, as in the case with sulfonamide, initial phototoxic reactions to chlorpromazine may be followed by true allergic sensitization. Although large doses of sunburn radiation (290-310 nm) may be required to elicit the more common phenothiazine phototoxic reactions, Sams, Epstein, Kligman, and Breit demonstrated positive photopatch tests with longwave ultraviolet light as well.IS' i« The antihistamine promethazine is a phenothiazine derivative closely related to chlorpromazine (Fig. 4). Photo cross-reaction between promethazine and chlorpromazine has been demonstrated.^^^ ^o Positive photopatch testing to nonphenothiazine antihistamines also has been elicited with a carbon arc lamp (2500-7000A) and diphenhydramine, bromodiphenhydramine, chlorpheniramine and carbinoxamine." Tetracyclines Demethylchlortetracycline was introduced for general clinical use in 1958. Soon thereafter, numerous reports of photosensitive reactions to the drug ap-
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DRUG PHOTOSENSITIZATION • 7arra(f
CH3
OH
321
OH
6
0H°" 0 CH3
TETRACYCLINE OH
Fig. 5. All of the tetracyclines except minocycline have significant photosensitizing potential.
OH
0
OH
CH3
N
0
CHLORTETRACYCLINE .H3
CH3
CONH, OH
0
OH
0
DOXYCYCLINE
peared.32,33 vVith attention thus focused on the photosensitizing capacity of demethylchlortetracycline, closer scrutiny of other tetracyclines revealed photosensitive reactions and photoonycholysis due to other tetracycline derivatives.•^•* Originally, it was thought that the presence of a chlorine atom at position 7 and the absence of a methyl radical at position 6 were prerequisites for photosensitizing capacity.-^-'' However, later studies revealed that doxycycline, which differs from the basic tetracycline structure only in the absence of a hydroxyl group at position 6, has a significant phototoxic potential-^*^ (Eig. 5). Studies of demethylchlortetracycline by Orentreich, Harber, Tromavitch, Baer, Kligman, and others'"-'' indicated that the mechanism of photosensitization was phototoxicity rather than photoallergy. They based this conclusion on the high incidence of photosensitive reactions with demethylchlortetracycline, the sunburn-like reaction with no eczematization in photopatch test sites, and the quick reversibility of photosensitivity upon discontinuing the drug. Later, however, Tromavitch and Jacobs reported a pa-
OH
0
OH
OHll 0
MINOCYCLINE
tient in whom a photoeruption developed while taking oxytetracycline, in whom photosensitivity persisted 6 months after discontinuing the drug, and in whom phototest sites were eczematous in nature, accompanied by distant flares of eczematous dermatitis.^" Thus, it appears that, although the vast majority of tetracycline-photosensitive reactions are phototoxic in nature, development of true photoallergic hypersensitivity to tetracycline occasionally may be seen. Some studies to determine the action spectrum for tetracycline photosensitive reactions indicate that middle range ultraviolet light (290-320 nm; UVB) is responsible.^' However, these studies were done with artificial light sources which apparently produced insufficient amounts (320-400 nm; UVA) of longwave ultraviolet light to induce reactions, since patients have been reported who developed photosensitive eruptions to demethylchlortetracycline through window glass^-' •'•' Other studies demonstrated phototoxic reactions to intradermal tetracycline and demethylchlortetracycline in human volunteers with natural sunlight
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through window glass, but not with artificial light sources through window glass or Mylar.'*'*' ''•'' Stratigos and Magnus""' demonstrated with a monochromator positive phototoxic reactions to intradermal demethylchlortetracycline with light between 350 and 420 nanometers. Griseofuivin Patients taking griseofuivin, when exposed to significant doses of natural sunlight, will develop exaggerated sunburn reactions. Lamb and colleagues^'' demonstrated, in patients taking griseofuivin, enhanced erythema responses to artificial UVB and 2-f erythema responses to artificial ultraviolet light through window glass.'•" Administration of griseofuivin to mice induces increased hepatic synthesis of protoporphyrin and increased fecal excretion of protoporphyrin and coproporphyrin.4R. ^g j h e drug also induces synthesis of delta-aminolevulinic acid synthetase in tissue cultures of chick embryo liver cells.so Hence, it has been proposed that the photosensitivity induced by griseofuivin might be due to induction of an artificial erythropoietic protoporpbyria-like state. However, it has never been conclusively demonstrated that oral administration of griseofuivin to humans results in the same induction of excess porphyrin synthesis as seen in mice.^'' ^2 The maximum absorption spectrum of griseofuivin falls in the sunburn spectrum. Thus, it seems more tenable to ascribe the photosensitivity induced by griseofuivin to a simple photodynamic mechanism. • Psoralens
As already recounted, naturally occurring psoralens were known for their photosensitizing capacity in ancient
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Vpl. 15
India, Central Asia and Egypt. More recently, modern physicians have become aware of the hyperpigmented berloque dermatitis seen in women caused by psoralens in perfume. And, in 1951, bullous photoreactions were reported among celery harvesters who contacted psoralens in pink rot fungus on celery plants." Most phototoxic reactions discussed earlier in this paper are photodynamically induced by a photoactive molecule which absorbs light energy and then contributes that energy to an oxidation reaction involving molecular oxygen. Psoralen phototoxicity, however, is partially inhibited by the presence of molecular oxygen.54 The psoralen molecule in the presence of longwave ultraviolet light photo-binds to thymine in cellular DNA and thus shuts down DNA synthesis." Although the psoralen absorption peaks are at 250 and 300 nm the action spectrum for psoralen phototoxicity falls in a range between 320 and 370 nm.''^''^ The usual phototoxic reaction induced by psoralen and longwave ultraviolet light is a non-eczematous, enhanced sunburn erythema which reaches its peak between 48 and 72 hours after exposure. Curiously, however, eczematous photoallergic reactions to 8-methoxypsoralen have been reported as well.^' Psoralens have been used for many years in the treatment of vitiligo. In the last 3 years, psoralens and longwave ultraviolet light have been found useful in the treatment of psoriasis. Originally, 8-methoxypsoralen was applied topically to psoriatic plaques and irradiated with black light. Although this mode of therapy induced resolution of psoriatic plaques, it also left a residual cosmetically objectionable hyperpigmentatjon.co- Cl Most recently, 8-methoxypsoralen has been administered orally and
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DRUG PHOTOSENSITIZATION • Jarratt
followed by longwave ultraviolet irradiation in a closet-like light box.'*- This mode of therapy for psoriasis is still under investigation; however, initial studies are encouraging. Miscellaneous Drugs Both of the commonly used artificial sweeteners have induced photosensitive reactions. Cyclamates caused eczematous photoeruptions in patients in whom the lesions could be reproduced by oral ingestion of cyclamates and light or by photo-patch testing with cyciamates. The same photosensitive reactions could not be induced in normal volunteers,'''-''^ Because of the low incidence of photoreactions to cyclamates and because of inability to reproduce similar lesions in normal volunteers, it can be assumed that the reported reactions are photoallergic in nature. Four patients are reported to have developed photosensitive reactions while using saccharin.'''^ Photoxic bullous eruptions due to nalidixic acid may develop after extensive sun exposure. In some cases, blisters continue to form for weeks after the drug is discontinued.^''-'5^ Drug Names bromodipbenbydramine: Ambrodryl carbinoxmine: Twiston-RA carbutamide: Nadisan chlorpromazine: Thorazine chlorpro[3amide: Diabinese , demetbylchlortetracycline: Declomycin dipbenbydramine: Benadryl doxycycline: Doxy II, Vibramycin 8 MOP {8-methoxypsoralen): Oxsoralen mepazine: Pacatal minocycline: MInocin, Vectrin nalidixic acid: NegGram procblorperazine: Compazine promethazine: Phenergan tolbutamide: Orinase trioxsalen {4, 5', 8-trimethylpsoralen): Trisoralen vinblastine: Velban
323
References 1, Fitzpatrick, T, B,, and Pathak, M, A,, Historical aspects of methoxsalen and otber furocoumarins, J, Invest, Dermatol, 32:229, 1959, 2, Fahmy, I, R,, and Abu-Sbady, H,, Ammi majus linn: Pbarmacognostical study and isolation of crystalline constituent, Ammoidin, Quart. J, Pharm, Pharmacol, 20:281, 1947, 3, Kalivas, J,, A guide to tbe problem of photosensitivity, JAMA 209:1706, 1969, 4, Sams, W, M,, Photosensitizing therapeutic agents, JAMA 174:2043, 1960, 5, Kirscbbaum, B, A,, and Beerman, H,, Pbotosensitization due to drugs. Am, J, Med Sci 248:445, 1964, 6, Harber, L, G,, and Baer, R, L,, Pathogenic mechanism of drug-induced photosensitivity, J, Invest, Dermatol, 58:327, 1972, 7, Storck, H,, Photoallergy and pbotosensitivity. Arch, Dermatol, 91:469, 1965, 8, Freeman, R, G,, and Knox, J, M,, The action spectrum of photocontact dermatitis caused by halogenated salicylanilide and related compounds. Arch, Dermatol, 97:130, 1968, 9, Epstein, S,, Pbotoallergy and primary pbotosensitivity to sulfanilamide, J, Invest, Dermatol, 2:43, 1939, 10, Bloom, H, F,, Studies of photosensitivity due to sulfanilamide, J, Invest, Dermatol, 4-159 1941, 11, Burckbardt, W,, Untersucbungen uber die photoaktivitat einiger sulphanilamide, Dermatologica 83:63, 1941, 12. Aoki, K,, and Saito, T,, Studies on the mechanism of photosensitivity caused by sulfa drugs. In Sunlight and Man, Edited by Fitzpatrick, T, B. Tokyo, University of Tokyo Press, 1974, pp, 431-444, 13. Sulser, H,, Photocbemische kupplung des sulfanilamids und aromatiscber amine an eiweiss und andere bocbmolekulare verbindungen, Arcb, Klin, Exper, Dermatol, 215: 266, 1962, 14, Willis, I,, and Kligman, A, M,, Diagnosis of pbotosensitization reactions by the scotch tape provocative patch test. J. Invest. Dermatol, 51:116, 1968, 15, Kligman, A, M,, and Breit, R,, Identification of pbototoxic drugs by buman assay. J. Invest, Dermatol, 51:90, 1968, 16. Burckbardt, W,, and Sutter, T. (Photoallergic drug exanthema caused by bydrocblorothiazide), Z, Haut Geschlechtskr. 34:105, 1963. 17. Harber, L G,, Lashinsky, A, M., and Baer, R, L,, Skin manifestations of pbotosensitivity due to cblorthiazide and hydrocblorothiazide, J, Invest, Dermatol, 33:83, 1959,
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18. Sams, W. M., Jr., and Epstein, J. H., The experimental production of drug phototoxicity in guinea pigs. I. Using sunlight. J. Invest. Dermatol. 48:89, 1967. 19. Burckhardt, W., Burckhardt, K., and SchwarzSpeck, M., Photoallergic eczemas caused by carbutamide (Nadisan). Schweiz. Med. Wchnschr. 87:954, 1957. 20. Sams, W. M., Photosensitizing therapeutic agents. JAMA 174:2043, 1960. 21. Hitselberger, J. F., and Fosnaugh, R. P., Photosensitivity due to chlorpropamide. JAMA 180:62, 1962. 22. De Eds, F., Wilson, R. H., and Thomas, J. O., Photosensitization by phenothiazine. JAMA 114:2095, 1940. 23. Winkelman, N. W., Jr., An appraisal of chlorpromazine. Am. J. Psychiatr. 113:961, 1957. 24. Epstein, J. H., Brunsting, L. A., Petersen, M. C, and Schwarz, B. E., Study of photosensitivity occurring with chlorpromazine therapy. J. Invest. Dermatol. 28:329, 1957. 25. Ayd, F. J., Jr., The dermatologic and systemic manifestations of chlorpromazine hypersensitivity. J. Nerv. Mental Dis. 124:84, 1956. 26. Cahn, M. M., and Levy, E. J. Ultraviolet light factor in chlorpromazine dermatitis. Arch. Dermatol. Syphilol. 75:38, 1957. 27. Cohen, 1. M., and Nash, J. B., Photosensitization by chlorpromazine. Psychlat. Res. Rep. 1:11, 1955. 28. Epstein, S., Chlorpromazine photosensitivity: Phototoxic and photoallergic reactions. Arch. Dermatol. 98:354, 1968. 29. Epstein, S., and Rowe, R. J., Photoallergy and photocross-sensitivity to phenergan. J. Invest. Dermatol. 29:319, 1957. 30. Newill, R. C. D., Photosensitivity caused by Promethazine. Br. Med. J. 2:359, 1960. 31. Schreiber, M. M., and Naylor, L. Z., Antihistamine pbotosensitivity. Arch. Dermatol. 86:58, 1962. 32. Morris, W. E., Photosensitivity due to tetracycline derivative. JAMA 172:1155, 1960. 33. Falk, M. S., Light sensitivity due to demethychlortetracycline. JAMA 172:1156, 1960. 34. Segal, B. M., Photosensitivity, nail discoloration and onycholysis: Side effects of tetracycline therapy. Arch. Int. Med. 112:165, 1963. 35. Tanioku, K., and Ono, K., Phototoxic and photoallergic problems. In Sunlight and Man. Edited by Fitzpatrick, T. B. Tokyo, University of Tokyo Press, 1974, pp. 483-493.
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36. Frost, P., Weinstein, C. D., and Comez, E. C, Phototoxic potential of minocycline and doxycycline. Arch. Dermatol. 105:681, 1972. 37. Orentreich, N., Harber, L. C, and Tromovitch, T. A., Photosensitivity and photo-onycholysis due to demethylcblortetracycline. Arch. Dermatol. 83:730, 1961. 38. Harber, L. C, Tromovitch, T. A., and Baer, R. L., Studies on photosensitivity due to demethylchlortetracycline. J. Invest. Dermatol. 37:189, 1961. 39. Kligman, A. M., Declomycin Compendium. Pearl River, New York, Lederle Pharmaceuticals, 1962, p. 49. 40. Tromovitcb, T. A., and Jacobs, P. H., Photosensitivity to oxytetracycline. Ann. Int. Med. 58:529, 1963. 41. Sams, W. M., The experimental production of drug phototoxicity in guinea pigs. II. Using artificial light sources. Arch. Dermatol. 94:773, 1966. 42. Saslaw, S., Demethylchlortetracycline pbototoxicity. N. EngI. J. Med. 264:1301, 1961. 43. Fubrmann, D. L., and Drowns, B. V., Demethylchlortetracycline: Clinical aspect of its use in dermatology. Arch. Dermatol. 82:244, 1960. 44. Schorr, W. F., and Monash, S., Photo-irradiation studies of two tetracyclines. Arch. Dermatol. 88:440, 1963. 45. Maibach, H. I., Sams, W. M., and Epstein, J. H., Screening for drug toxicity by wavelengths greater than 3100 A. Arch. Dermatol. 95:12, 1967. 46. Stratigos, J. D., and Magnus, I. A., Photosensitivity by demethylchloretracycline and sulphanilamide. Br. J. Dermatol. 80:391, 1968. 47. Lamb, J. H., Jones, P. E., Morgan, R. J., et al.. Further studies on light sensitive eruptions. Arch. Dermatol. 83:568, 1961. 48. DeMatteis, F., and Rimington, C, Disturbance of porphyrin metabolism caused by griseofulvin in mice. Br. J. Dermatol. 75:91, 1963. 49. Lockhead, A. C, Dagg, J. H., and Coldberg, A., Experimental griseofulvin porphyria in adult and fetal mice. Br. J. Dermatol. 79:96, 1967. 50. Cranick, S., The induction in vitro of the synthesis of delta-aminolevulinic acid synthetase in chemical porpbyria: A response to certain drugs, sex hormones and foreign chemicals. J. Biol. Cbem. 241:1359, 1966. 51. Rimington, C, Morgan, P. N., Nicholls, K., et al., Criseofulvin administration and porphyrin metabolism. Lancet 2:318, 1963.
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DRUG PHOTOSENSITIZATION • larratt
52. Watson, C. |., Lynch, F., Bossenmaier, I., and Cardinal, R., Criseofulvin and porphyrin metabolism. Arch. Dermatol. 98:451, 1968. 53. Birmingham, D. ]., Key, M. M., Tubich, C. E., and Perone, V. B., Phototoxic bullae among celery harvesters. Arch. Dermatol. 83:73, 1961. 54. Matbews, M. M., Comparative study of lethal photosensitization of Carcina lutea by 8metboxypsoralen and by Toluidine blue. J. Bacteriol. 85:322, 1963. 55. Pathak, M. A., Kriamer, D. M., and Fitzpatrick, T. B., Photobiology and photochemistry of furocoumerius. In Sunlight and Man. Edited by Fitzpatrick, T. B. Tokyo, University of Tokyo Press, 1974, pp. 335-368. 56. Buck, H. W., Magnus, I. A., and Porter, A. D., The action spectrum of 8-methoxypsoralen for erythema in human skin. Br. J. Dermatol. 72:249, 1960. 57. Pathak, M. A., Mechanisms of psoralen pbotosensitization. J. Invest. Dermatol. 37: 397, 1961. 58. Owens, D. W., Glicksman, I. M., Freeman, R. C , and Carnes, R., Biologic action spectra of 8-metboxypsoralen determined by monocbromatic light. J. Invest. Dermatol. 51:435, 1968. 59. Fulton, J. E., and Willis, I., Photoallergy to methoxsalen. Arcb. Dermatol. 98:445, 1968.
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60. Walter, J. E., and Voorhees, J. J., Psoriasis improved by psoralen plus black light. Acta Derm. Venereol. 53:469, 1973. 61. Weber, C , Combined 8-methoxypsoralen and black light therapy of psoriasis. Br. J. Dermatol. 90:317, 1974. 62. Parrish, J. A., Fitzpatrick, T. B., Tanenbaum, L., and Pathak, M. A., Pbotochemotherapy of psoriasis witb oral metboxsalen and longwave ultraviolet light. N. EngI. J. Med. 291:1207, 1974. 63. Lamberg, S. I., A new pbotosensitizer: The artificial sweetener cyciamate. JAMA 201: 747, 1967. 64. Yong, J. M., and Sanderson, K. V., Pbotosensitive dermatitis and renal tubular acidosis after ingestion of calcium cyciamate. Lancet 2:1273, 1969. 65. Kobori, ]., and Araki, H., Pbotoallergy in dermatology. J. Asthma Res. 3:213, 1966. 66. Kennedy, B., O'Quinn, S., Perret, W. |., et al., Pbototoxic and pbotoallergic skin reactions from modern drug tberapy. \. La. Med. Soc. 113:365, 1961. 67. Birkett, D. A., Garretts, M., and Stevenson, C. J., Pbototoxic bullous eruptions due to nalidixic acid. Br. J. Dermatol. 81:342, 1969. 68. Ramsay, C, and Obresbkova, E., Pbotosensitivity from nalidixic acid. Br. J. Dermatol. 91:523, 1974.
Skip another two thousand years: staphylococci are being fought with copper to this very day. There is a staphylococcal skin infection called impetigo. In France at least, a very popular—and, 1 am told, practically indispensable—prescription against impetigo is the Eau Dalibour. It was devised around the year 1700 by Monsieur Jacques Dalibour, surgeon general to the army of Louis XIV. Its principal ingredients are copper and zinc, and it worked like a charm for "all Manners of Wounds, Cuts, Slashes by Sword or Sabre, and Injuries by all Cutting and Bruising Devices."—Majno, C, The Heating Hand: Man and Wound in the Ancient World. Cambridge, MA, Harvard University Press, 1975, p. 113-115.
